Month: November 2012

O. Von Corven “The Great Library of Alexandria”. Image (obtained from Wikimedia Commons) is in the public domain.

I have a note written on parchment by my ancestor Eliezer, who lived in Alexandra Egypt, in which he describes his father Yitzchak taking him to the grand library in Alexandria Egypt before it was burnt by Julius Caesar. He was awed by the cabinets containing innumerable scrolls lining the halls from floor to ceiling, which he was told contained all of human knowledge. Little did he know! I am his direct and spiritual descendent, and I must share my awe and admiration for a new disease gene compilation in progress by the direct descendent of the library of Alexandria, the National Library of Medicine at NIH in Bethesda, Maryland. It is worth exploring the site. I searched for some of diseases: tyrosinemia II , epidemolysis bullosa, psoriasis, and dyskeratosis congenita. The pages for these diseases rapidly loaded, with a number of entries from a broad range of databases. The page is in the standard ”entrez page” format and has, in addition, links to extensive literature, sequence data, molecular interactions, SNPS, comparative species data, and even a direct link to some blast searches. The pages with cross-species homologies are especially well done. I loved the three-dimensional color pictures of molecules (e.g., psoriasin), which I easily downloaded and put into a power point presentation.

“Clinvar” provides lots of variant sequence information in a single location and allows integration of molecular and clinical findings for patients, students and researchers.

This site is very worth bookmarking and exploring for your diseases of interest.

Many of the structural and enzymatic components of the epidermis are destroyed during the final cataclysmic stages of epidermal differentiation. Keratins and filaggrins form amino acids and contribute to the water-retaining ability of the epidermis and its” natural moisturizing functions”. Many of the synthetic enzymes of the epidermis are also metabolized. After proteolysis, at least one synthetic molecule forms a 30-amino acid peptide that has both immune-modulating and antifungal properties (Wagener et al, 2012 — JID.2012.254). Many decades ago antibiotics were found in the environment or in soil samples. Now there is a new paradigm looking for “natural” anti-microbial molecules made by the body.

GAPDH (glyceraldehyde-3-phosphate dehydrogenase) is important for glycolysis, transcription and apoptosis. There is a 30-amino acid fragment from its N-terminal that is internalized by Candida albicans, leading to fungal cell death. What great recycling! After GAPDH has fulfilled its synthetic role, at least one portion of the molecule can protect the epidermis by exterminating at least one yeast species — an organism that is a nuisance for some individuals and a serious pathogen for others. A great example of both the wisdom and the economy of the body. If a molecule gets beat up and can’t fulfill its original function, buff it up (in this case: cut off a segment) and apply it to another function. Wagener et al report interesting details on the discovery and the action of the 30-amino peptide from GAPDH. More importantly, this model expands our thinking on how to look for epidermal molecules that may have more than one physiological function.

Liver X receptors (LXRα & LXRβ) represent a subfamily of thyroid hormone receptor-like nuclear receptors that regulate cholesterol, fatty acid, and glucose homeostasis via endogenous oxysterol ligands. These receptors form heterodimers with 9-cis retinoic acid receptor as an obligate partner, and LXR agonists show anti-inflammatory properties. LXR have been detected in human skin, where they play a role in epidermal proliferation, differentiation and barrier permeability. Their role in skin pathology remains unclear, however.

Previously the lab of Davinder Parsad reported that LXRα expression in human melanocytes is significantly higher in perilesional skin than in normal skin of vitiligo patients (Exp Dermatol 19:62-64, 2010). In this new study (1), they report that increased LXRα expression in vitiligo perilesional skin is associated with a markedly reduced MMP (-1, -2, -9) expression, and that LXRα gene knockdown in vitro increases MMP expression by melanocytes. Melanocyte adhesion to collagen IV was reduced by the LXRα natural ligand 22(R)-hydroxy-cholesterol, as was the incidence of melanocyte apoptosis.

These important findings offer new insights into the fate of differentiated melanocytes targeted in active vitiligo. Whether LXRα expression in vitiligo can be induced by oxidative stress will be fascinating to explore.

The skin’s best known protection mechanism against ultraviolet (UV) radiation is the production of melanin. For individuals with fair skin or albinism this intrinsic ability to shield cells from UV radiation is blunted or absent.

The D’Orazio lab now reports on the mechanisms and efficiency of a pigment-independent UV protection mechanism (1). Using mice humanized for epidermal Scf expression to maintain a pool of interfollicular melanocytes, together with mutant Mc1r or Tyrosinase alleles to make the models specific for fair or albino skin, the authors show that either forskolin treatment or UV irradiation promote epidermal proliferation. They go on to show that the resulting epidermal thickening alone, even in the absence of melanin production, provides significant protection against UV penetration into the skin and resulting cell damage. Keratinocyte growth factor (Kgf/Fgf7), a known stimulator of melanin uptake by keratinocytes, appears to be the driver of this epidermal thickening through induction of keratinocyte proliferation.

These insights implicate Kgf as a stimulator of diverse cellular mechanisms that constitute the skin’s full photoprotective response and suggest new approaches to aid skin photoprotection in individuals with weak or absent melanization.

The hair follicle is surrounded by a variety of cell types that deliver a plethora of signals to orchestrate hair follicle homoeostasis. A recent viewpoint essay by Schmidt & Horsley (1) highlights the poorly understood and insufficiently investigated, but likely important communication between intradermal adipocytes and the hair follicle.

The authors first explain the anatomical prerequisite for their concept, i. e., the morphological and metabolic difference between the subcutaneous white adipose tissue and intradermally located adipocytes, the latter oscillating in their expansion during hair follicle cycling. Secondly, mutant mice strains with defects in adipocytes and an abnormal hair phenotype – e. g., the genetic mouse model lacking Early B-cell factor 1 (Ebf1-/-) – are discussed. This is followed by emphasizing the role of adipocyte-derived factors and classical adipokines like BMP2, leptin or adiponectin which regulate stem cell activity and cycling of the hair follicle. Finally, examples of lipid-associated human diseases are provided in which hair follicle homoeostasis is disrupted.

In summary, this viewpoint strongly encourages further research that explores the fascinating communication and interplay between intradermal adipocytes and the hair follicle.

The ECS and its receptors (cannabinoid receptors CB1 and CB2) impact on skin inflammation and sensory output and are increasingly appreciated as key regulators of mast cell, keratinocyte, and sebocyte functions. The Hachem lab (Brussels) now shows that the control of epidermal barrier function ranks among the expanding range of ECS tasks in murine skin physiology (1).

The authors show by examining knock-out mice that CB1 stimulation by endogenous agonists is required for rapid permeability recovery after tape stripping in vivo, while CB2-mediated signaling retards barrier repair and associated keratinocyte terminal differentiation events. This differential regulation of the epidermal barrier by the two ECS key receptors may serve as a finely tunable, intracutaneous fast-response system to environmental stressors.

These important findings also caution against the therapeutic use of CB2 agonists when treating skin diseases where the barrier already is defective and invite the speculation that, long before their adoption for purposes of central nervous signaling and computing, endocannabinoids and their receptors developed during evolution primarily to regulate vital epithelial functions.

The complex multi-directional interplay among various skin-derived cells is essential for the normal homeostatic function of the skin. Two recent Experimental Dermatology papers explore the effect of humoral factors produced by human follicular keratinocytes and sebocytes on hair growth.

Lee MH et al. (1) have shown that treating dermal papilla cells and dermal sheath cells with conditioned medium obtained from follicular keratinocytes (FKCM) resulted in induction of a greater number of hair follicles in patch assays and chamber grafts. Lee WJ et al. (2), on the other hand, used conditioned media obtained from either normal sebocytes or cells from nevus sebaceous lesions. They concluded that conditioned medium of nevus sebaceous sebocytes (but not of normal cells) decreased survivability and the number of dermal papilla cells and outer root sheath cells.

The two groups also performed microarray experiments. This analysis revealed that whereas the increased trichogenicity by FKCM coincided with the activation of the BMP and β-catenin signaling pathways (1), the decreased survival of hair follicle-derived cells by diseased sebocyte-conditioned medium could be linked to the production of hair growth suppressing factors (FGF5, Dickkopf-1, IL-4, IL-6, TGFβ1 and β2, etc).

Both studies highlight the indispensable regulatory role of the cutaneous local tissue micro-environment, and therefore, may encourage one to systematically explore the putative cross-talk among the different skin-derived cells. This would open new avenues for the identification of novel players and mechanisms in the (patho)physiology of hair growth and, in a wider sense, skin (patho)physiology in general.